Theoretical exploration of the binding selectivity of inhibitors to BRD7 and BRD9 with multiple short molecular dynamics simulations.
Theoretical exploration of the binding selectivity of inhibitors to BRD7 and BRD9 with multiple short molecular dynamics simulations.
复制标题
通过多次短分子动力学模拟理论探索抑制剂对 BRD7 和 BRD9 的结合选择性
作者：
含溴结构域蛋白7和9（BRD7和BRD9）已被认为是治疗人类癌症和其他疾病的临床药物设计的潜在靶标。通过多个短分子动力学模拟和结合自由能预测，研究了3种抑制剂4L2、5U6和6KT对BRD7和BRD9的结合选择性。结果表明，与5U6和6KT相比，4L2与BRD7的结合能力优于BRD9，而5U6和6KT与BRD9的结合能力优于BRD7。此外，基于残差的自由能分解的估计还识别出四个常见的残差对，包括（F155，F44），（V160，V49），（Y168，Y57）和（Y217，Y106）in（BRD7，BRD9）与4L2，5U6和6KT产生明显的结合差异，这主要驱动4L2，5U6，6KT到BRD7和BRD9。从轨迹分析产生的动态信息也表明，抑制剂结合影响结构的灵活性和运动模式，这是负责对BRD7和BRD9的4L2，5U6和6KT的部分选择性。根据我们的预期，该研究在理论上为设计对BRD7和BRD9具有高选择性的双重抑制剂提供了有用的提示。
Bromodomain-containing proteins 7 and 9 (BRD7 and BRD9) have been considered as potential targets of clinical drug design toward treatment of human cancers and other diseases. Multiple short molecular dynamics simulations and binding free energy predictions were carried out to decipher the binding selectivity of three inhibitors 4L2, 5U6, and 6KT toward BRD7 and BRD9. The results show that 4L2 has more favorable binding ability to BRD7 over BRD9 compared to 5U6 and 6KT, while 5U6 and 6KT possess more favorable associations with BRD9 than BRD7. Furthermore, estimations of residue-based free energy decompositions further identify that four common residue pairs, including (F155, F44), (V160, V49), (Y168, Y57) and (Y217, Y106) in (BRD7, BRD9) generate obvious binding differences with 4L2, 5U6, and 6KT, which mostly drives the binding selectivity of 4L2, 5U6, and 6KT to BRD7 and BRD9. Dynamic information arising from trajectory analysis also suggests that inhibitor bindings affect structural flexibility and motion modes, which is responsible for the partial selectivity of 4L2, 5U6, and 6KT toward BRD7 and BRD9. As per our expectation, this study theoretically provides useful hints for design of dual inhibitors with high selectivity on BRD7 and BRD9.
登录
查看更多内容
影响因子：
5
作者：
Chen, Jianzhong;Yin, Baohua;Sun, Haibo
通讯作者：
Sun, Haibo
从绝对结合自由能计算中的配体选择性预测。
影响因子：
15
作者：
Aldeghi M;Heifetz A;Bodkin MJ;Knapp S;Biggin PC
通讯作者：
Biggin PC
影响因子：
3.3
作者：
Chen, Jianzhong;Liu, Xinguo;Zhang, Qinggang
通讯作者：
Zhang, Qinggang
影响因子：
4.4
作者：
ESSMANN, U;PERERA, L;PEDERSEN, LG
通讯作者：
PEDERSEN, LG
影响因子：
5.2
作者：
Bell, Catherine M.;Raffeiner, Philipp;Vogt, Peter K.
通讯作者：
Vogt, Peter K.